Subarachnoid hemorrhage may be caused by trauma or by non-traumatic incidents, such as a ruptured intracranial aneurysm, arteriovenous malformation, or vasculitis. Cerebral arterial vasospasm is the leading cause of morbidity and mortality in patients surviving subarachnoid hemorrhage (SAH). Oxyhemoglobin appears to be responsible for vasospasm after SAH. Much existing evidence suggests that oxyhemoglobin is the clinically-relevant vasospastic agent. The presence of high concentrations of extracellular oxyhemoglobin in the cerebrospinal fluid (CFS) correlates with the presence of spasm in primates [Macdonald et al., Stroke 22:971-982 (1991)].
Concentrations of extracellular oxyhemoglobin are highest on post-SAH days 4 to 7, which corresponds with the onset of vasospasm. Oxyhemoglobin is no longer detectable in the CSF 14 to 21 days after SAH, which corresponds with resolution of vasospasm. Furthermore, intact erythrocytes are inert, whereas lysed erythrocytes are vasospastic, in vitro and in vivo. Lastly, oxyhemoglobin is vasospastic, whereas the oxidized methemoglobin is not.
The results of some experiments suggest that the iron in oxyhemoglobin causes vasospasm by generating free radicals and lipid peroxides.
Iron catalyzes the production of free radicals, which can cause damage to vascular smooth muscle, endothelial cells, and perivascular nerve endings, each an active participant in the normal vasoregulatory response [Macdonald et al., Stroke 22:971-982 (1991)]. Investigators have previously examined the therapeutic potential of iron chelators, oxidizing agents, and free radical scavengers, but with limited success.
Studies with ferric iron chelators such as deferoxamine in potential therapies for vasospasm have had only limited success [Harada et al., J. Neurosurg. 77:763-767 (1992)], [Vollmer et al., Neurosurgery 28:27-32 (1991)]. Deferoxamine has many shortcomings as a potential preventive therapy for delayed vasospasm. Deferoxamine has only limited penetrability of the blood-brain barrier, and adequate CSF levels cannot be achieved before toxic systemic effects appear [Peters et al., Biochem. Pharmacol. 15:93-109 (1966)], [Oubidar et al., Free Radical Biology and Medicine 16:861-867 (1994)]. Deferoxamine acts mainly extracellularly and chelates only free iron, and not heme or ferritin-bound iron. Furthermore, deferoxamine has a much greater affinity for ferric iron (Fe.sup.+3) than for ferrous iron (Fe.sup.+2) (the deferoxamine-iron stability constants are 10.sup.31 for Fe.sup.+3 and 10.sup.2 to 10.sup.14 for Fe.sup.+2). Therefore, deferoxamine acts only extracellularly and on unbound iron, and it does not chelate the ferrous state of iron responsible for free radical damage and possibly also responsible for the "sink effect."
Others propose that vasospasm results from a regional disruption in the balance of both constrictive and dilatory vascular regulation.
Oxyhemoglobin may induce damage by binding to nitric oxide (NO) molecules and locally limiting the availability of NO for vasodilation, in the so-called "sink effect" [Moncada et al., NeuroReport 3:530-532 (1992)].
Vasodilation is normally maintained by NO [Moncada et al., NeuroReport 3:530-532 (1992)]. Hemoglobin has a strong affinity for NO, binding to NO 1,500-fold more readily than to oxygen. NO normally binds to a ferrous heme moiety in the enzyme guanyl cyclase (which catalyzes the conversion of GTP to cyclic GMP in smooth muscle cells, and thereby decreases intracellular free calcium levels, causing vascular smooth muscle cells to relax). Since NO binds to the ferrous heme moiety of guanyl cyclase, it is possible that excess quantities of extracellular Fe.sup.+2, whether free or bound to heme in the perivascular space, may exert a powerful sink effect, limiting the availability of NO. This possibility is supported by the reversal of vasospasm by the intracarotid infusion of NO [Afshar et al., J. Neurosurg. 83:118-122 (1995)] from a short-lived donor of NO.